Unfavorable Tumor Research Articles

Immune-related 3-lncRNA signature with prognostic connotation in a multi-cancer setting

BackgroundAdvances in our understanding of the tumor microenvironment have radically changed the cancer field, highlighting the emerging need for biomarkers of an active, favorable tumor immune phenotype to aid treatment stratification and clinical prognostication. Numerous immune-related gene signatures have been defined; however, their prognostic value is often limited to one or few cancer types. Moreover, the area of non-coding RNA as biomarkers remains largely unexplored although their number and biological roles are rapidly expanding.MethodsWe developed a multi-step process to identify immune-related long non-coding RNA signatures with prognostic connotation in multiple TCGA solid cancer datasets.ResultsUsing the breast cancer dataset as a discovery cohort we found 2988 differentially expressed lncRNAs between immune favorable and unfavorable tumors, as defined by the immunologic constant of rejection (ICR) gene signature. Mapping of the lncRNAs to a coding-non-coding network identified 127 proxy protein-coding genes that are enriched in immune-related diseases and functions. Next, we defined two distinct 20-lncRNA prognostic signatures that show a stronger effect on overall survival than the ICR signature in multiple solid cancers. Furthermore, we found a 3 lncRNA signature that demonstrated prognostic significance across 5 solid cancer types with a stronger association with clinical outcome than ICR. Moreover, this 3 lncRNA signature showed additional prognostic significance in uterine corpus endometrial carcinoma and cervical squamous cell carcinoma and endocervical adenocarcinoma as compared to ICR.ConclusionWe identified an immune-related 3-lncRNA signature with prognostic connotation in multiple solid cancer types which performed equally well and in some cases better than the 20-gene ICR signature, indicating that it could be used as a minimal informative signature for clinical implementation.

Local control after palliative external beam radiotherapy for bone metastases in patients with favorable prognosis.

Advancement in systemic therapy has increased the importance of local control (LC) of bone metastatic sites treated with radiotherapy in intermediate-term survivors (surviving ≥1 year). To establish individualized radiotherapy for bone metastases, factors affecting LC of bone metastases treated with traditional fractionated moderate dose palliative radiotherapy (FMRT) in intermediate-term survivors were evaluated. Between January 2010 and December 2019, 317 lesions in 240 patients treated with FMRT for bone metastases surviving for at least 1 year and followed-up with CT for at least 6 months were reviewed retrospectively. The median survival and radiographic follow-up times were 24 months (range, 12-123 months) and 20 months (range, 1-119 months), respectively. The median FMRT dose [biologically effective dose (BED)10] was 39.0 Gy (range, 28.0-71.7 Gy). Multivariate analysis revealed that age (≥70 years), non-vertebral bone metastasis, bone metastasis from moderate and unfavorable primary tumor sites (esophageal, colorectal, hepatobiliary/pancreatic, kidney/ureter and sarcoma/melanoma cancers), and no administration of post-FMRT bone-modifying agents (BMAs) were unfavorable factors for LC of bone metastasis. The 2-year LC rates for FMRT doses (BED10) ≤39.0 Gy and >39.0 Gy were 90 and 87%, respectively. The 2-year LC rates of patients administered and not administered post-FMRT antineoplastic agents (ATs) were 91 and 78%, respectively. The sites of bone metastasis and primary tumors, and post-FMRT BMAs were factors associated with LC of bone metastasis in long-term survivors. However, a FMRT dose (BED10) ≥39.0 Gy and post-FMRT ATs were not significant factors.

Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.

Pan-keratin Immunostaining in Human Tumors: A Tissue Microarray Study of 15,940 Tumors.

To evaluate the efficiency of pan-keratin immunostaining, tissue microarrays of 13,501 tumor samples from 121 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. In normal tissues, strong pan-keratin immunostaining was seen in epithelial cells. Staining intensity was lower in hepatocytes, islets of Langerhans, and pneumocytes but markedly reduced in the adrenal cortex. Pan-keratin was positive in ≥98% of samples in 62 (83%) of 75 epithelial tumor entities, including almost all adenocarcinomas, squamous cell and urothelial carcinomas. Only 17 of 121 tumor entities (13%) had a pan-keratin positivity rate between 25% and 98%, including tumors with mixed differentiation, endocrine/neuroendocrine tumors, renal cell carcinomas, adrenocortical tumors, and particularly poorly differentiated carcinoma subtypes. The 15 entities with pan-keratin positivity in 0.9%-25% were mostly of mesenchymal origin. Reduced/absent pan-keratin immunostaining was associated with high UICC stage (p = 0.0001), high Thoenes grade (p = 0.0183), high Fuhrman grade (p = 0.0049), advanced tumor stage (p < 0.0001) and lymph node metastasis (p = 0.0114) in clear cell renal cell carcinoma, advanced pT stage (p = 0.0007) in papillary renal cell carcinoma, and with advanced stage (p = 0.0023), high grade (p = 0.0005) as well as loss of ER and PR expression (each p < 0.0001) in invasive breast carcinoma of no special type (NST). In summary, pan-keratin can consistently be detected in the vast majority of epithelial tumors, although pan-keratin can be negative a fraction of renal cell, adrenocortical and neuroendocrine neoplasms. The data also link reduced pan-keratin immunostaining to unfavorable tumor phenotype in in epithelial neoplasms.

Clinical, pathological and long-term oncologic outcomes of papillary type I vs. type II renal cell carcinoma.

Despite papillary renal cell carcinoma (pRCC) subtype represents the second most common histological renal tumor, controversial findings have been shown regarding its prognosis. Thus, we investigated the natural history of patients harbouring pRCC, focusing on its clinicopathological characteristics and long-term oncologic outcomes among pRCC subtypes. We identified 447 patients treated with either partial (PN) or radical nephrectomy (RN) for pRCC at a single tertiary centre, between 1994 and 2019. First, we explored differences in baseline and clinicopathological characteristics. Second, Kaplan-Meier plots investigated progression-free survival (PFS) and cancer-specific survival (CSS) differences among pRCC subtypes. Third, multivariable Cox-regression analyses (MVA) were used to assess predictors of clinical progression (CP) and cancer-specific mortality (CSM). Overall, 120 (27%) patients had symptoms at time of diagnosis. 263 (58.8%) vs. 184 (41.2%) patients underwent PN vs. RN. At histopathological evaluation, 243 (54.4%) harboured pRCC type I vs. 204 (45.6%) type II. pRCC type II more frequently showed higher tumor grade, tumor necrosis or lymphovascular invasion (all P<0.001). After a median follow-up of 51 months, 2.5% and 11% of patients had local relapse and CP, respectively. Kaplan-Meier plots revealed 93 vs. 83% 5-year PFS (P<0.001) and 96 vs. 89% 5-year CSS (P=0.01) for non-metastatic pRCC type I vs. II, respectively. At MVA, pRCC type II predicted higher risk of CP (Hazard ratio [HR]: 3.03, 95%CI 1.42-6.44; P=0.01), as well as of CSM (HR: 2.60, 95%CI 1.05-6.29; P=0.02), relative to pRCC type I. PRCC type II harbour more unfavorable tumor characteristics, such as higher tumor grade, more frequent tumor necrosis or lymphvascular invasion, which translates into worse long-term oncologic outcomes, compared with pRCC type I. Thus, patients harbouring pRCC type II may benefit from stricter follow-up, as well as earlier risk-based adjuvant therapies, based on potential worse oncologic outcomes in this patient population.

CXCL8 expression is associated with advanced stage, right sidedness, and distinct histological features of colorectal cancer.

CXCL8 is an inflammatory chemokine elevated in the colorectal cancer (CRC) tumour microenvironment. CXCR2, the major receptor for CXCL8, is predominantly expressed by neutrophils. In the cancer setting, CXCL8 plays important roles in neutrophil chemotaxis, facilitating angiogenesis, invasion, and metastasis. This study aimed to assess the spatial distribution of CXCL8 mRNA expression in CRC specimens, explore associations with clinical characteristics, and investigate the underlying biology of aberrant CXCL8 levels. CXCR2 expression was also assessed in a second cohort of unique CRC primary tumours and synchronously resected matched liver metastases. A previously constructed tissue microarray consisting of a cohort of stage I–IV CRC patients undergoing surgical resection with curative intent (n = 438) was probed for CXCL8 via RNAscope®. Analysis was performed using HALO® digital pathology software to quantify expression in the tumour and stromal compartments. Scores were assessed for association with clinical characteristics. Mutational analyses were performed on a subset of these patients to determine genomic differences in patients with high CXCL8 expression. A second cohort of stage IV CRC patients with primary and matched metastatic liver tumours was stained via immunohistochemistry for CXCR2, and scores were assessed for clinical significance. CXCL8 expression within the stromal compartment was associated with reduced cancer‐specific survival in the first cohort (p = 0.035), and this relationship was potentiated in right‐sided colon cancer cases (p = 0.009). High CXCL8 within the stroma was associated with driving a more stromal‐rich phenotype and the presence of metastases. When stromal CXCL8 scores were combined with tumour‐infiltrating macrophage counts or systemic neutrophil counts, patients classified as high for both markers had significantly poorer prognosis. CXCR2+ immune cell infiltration was associated with increased stromal invasion in liver metastases (p = 0.037). These data indicate a role for CXCL8 in driving unfavourable tumour histological features and promoting metastases. This study suggests that inhibiting CXCL8/CXCR2 should be investigated in patients with right‐sided colonic disease and stroma‐rich tumours.

Paclitaxel, ifosfamide, cisplatin (TIP) for the treatment of intermediateand poor-risk nonseminomatous germ cell tumors with an inadequate decrease in tumor markers: a phase II study

Purpose: To evaluate efficacy of TIP (paclitaxel, ifosfamid, cisplatin) in the 1st line treatment of germ cell tumors patients with unfavorable decline of serum tumor markers after 1 cycle of the standard regimen of chemotherapy. Patients and methods: In this phase II multicenter, nonrandomized trial, patients were enrolled from 4 centers of the Russian Federation. Patients were included if they were older than 18 years, had evidence of testicular, retroperitoneal, or mediastinal nonseminoma based on histologic findings or clinical evidence (high serum human chorionic gonadotropin or alpha-fetoprotein levels) that matched International Germ Cell Cancer Consensus Group (IGCCCG) intermediate and poor prognosis criteria. All patients got one cycle of BEP regimen (bleomycin 30 mg on days 1, 3, 5, etoposide 100 mg / m 2 on days 1–5, cisplatin 20 mg / m 2 on days 1–5). Patients with unfavorable serum tumor markers decline after the first cycle of chemotherapy at day 18–21 received four cycles of TIP regimen (paclitaxel 120 mg / m 2 on days 1–2, ifosfamide 1500 mg / m 2 on days 2–5, and cisplatin 25 mg / m 2 om days 2–5, granulocyte-colony stimulating factor 5 mg / kg on days 6–15). In the presence of a residual tumor larger than 1 cm and the technical possibility of its removal, surgical treatment was performed. The primary endpoint was 1-year progression-free survival. Results: Between 2017 and 2021, 28 patients were included in our study: seven patients with an intermediate prognosis according to IGCCCG classification and twenty-one with poor risk. Median follow-up was 15,5 months (range, 4,4–38,3 months). The 1-year progression-free survival and overall survival in intention-to-treat population were 76,6 % and 81,0 %, respectively. One-year progression-free survival and overall survival according IGCCCG classification were 100 % and 100 % for an intermediate risk patients and 68 % and 73,8 % for a poor risk, respectively. The favorable response rate (complete response + partial response with normalization STM) was observed in 19 (68 %) patients. During the follow-up period, disease progression was noted in 9 (32 %) patients, 7 (25 %) patients died, including one from an aggressive growing mature teratoma syndrome. Eleven (39 %) patients underwent surgical treatment: retroperitoneal lymph node dissection (55 %), mediastinal lymph node dissection (36 %), pulmonary resection (9 %). Pathological complete response was achieved in 6 (55 %) patients, mature teratoma — 2 (18 %), viable tumour — 3 (27 %). TIP showed acceptable safety profile and only in one case tumor lysis syndrome was observed. Conclusions: The TIP regimen may improve the results of treatment in the first line with unfavorable decrease of serum tumor markers after the first cycle of chemotherapy, which requires further study in a randomized trial.

Surgical strategy for metastatic spinal tumor patients with surgically challenging situation.

The incidence of spinal metastasis is increasing as cancer patients live longer owing to the improvement of cancer treatments. However, traditional surgery (TS) which fixates at least 2 levels above and 2 levels below the affected vertebrae is sometimes difficult to perform as it is burdensome to the patients. In this article, we introduce our experience and strategy in treating spinal metastasis, focusing particularly on challenging cases.We retrospectively reviewed the data of 110 patients who underwent spinal surgery for metastatic spinal tumors from April 2018 to March 2020. Among them, 5 patients who received anterior approach surgery were excluded. The remaining 105 patients were enrolled. In addition to TS, we also performed cervical pedicle screw, cervicothoracic junction fixation, thoracolumbar short fixation, and decompression surgery, depending on the characteristics of the tumor. The overall survival was analyzed, and the local tumor control rate was evaluated using magnetic resonance imaging. Perioperative clinical characteristics including Spine Oncology Study Group Outcomes Questionnaire, visual analog scale, Eastern Cooperative Oncology Group performance score, and Karnofsky Performance Score were also investigated.The overall survival rate was 57.9% at 1 year, and the local tumor control rate was 81.1% after surgery. There was a statistically significant difference according to the type of the tumor in the survival analysis: the overall survival rates were 72.7% for favorable tumors and 48.6% for unfavorable tumors at 12 months after surgery (P = .04). Spine Oncology Study Group Outcomes Questionnaire, visual analog scale, Eastern Cooperative Oncology Group performance score, and Karnofsky Performance Score was improved after surgery. All surgical methods, including TS, cervical pedicle screw, cervicothoracic junction fixation, thoracolumbar short fixation, and decompression surgery, showed good clinical and radiological outcomes.Optimized surgical methods show similarly good clinical outcomes in managing spinal metastasis as TS.

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Outcomes of adolescent and young patients with hepatocellular carcinoma after curative liver resection: a retrospective study

BackgroundThe risk of HCC is documented to be age-related. The outcomes of young HCC patients on postoperative prognosis are not well understood. The study aims to compare the characteristic differences between adolescent and young (AYA) and non-AYA HCC patients.MethodsWe performed a retrospective analysis of the clinical and pathological findings and the survival of 243 HCC patients who underwent operations between 2007 and 2018.ResultsThe AYA group had a higher AFP level and a higher prevalence of family history of HCC or other cancers than the non-AYA group (P < 0.01 and P < 0.05). AYA patients had more unfavorable pathological characteristics including bigger lesion size, microvascular invasion, portal vein invasion, and hepatic capsule invasion. They also had a more unfavorable Edmondson grade and less tumor capsule formation (P < 0.01). Age was an independent predictor of survival in HCC patients. AYA patients had poorer disease-free and overall survival than non-AYA patients did (P < 0.01). Patients under 30 years old had an even poorer disease-free survival than those aged 30–40 (P = 0.047).ConclusionsAYA patients exhibited a higher recurrence rate and disease-related death rate with more unfavorable pathological characteristics. Enhanced follow-up for young HCC patients should be applied.

Long Non-Coding RNA-TMPO-AS1 as ceRNA Binding to let-7c-5p Upregulates STRIP2 Expression and Predicts Poor Prognosis in Lung Adenocarcinoma.

BackgroundStriatin-interacting protein 2 (STRIP2), also called Fam40b, has been reported to regulate tumor cell growth. But the role of STRIP2 in lung adenocarcinoma (LUAD) has not been discovered clearly. Thus, the aim of our study is to explore the function and underlying mechanism of STRIP2 in LUAD.MethodsExpression of STRIP2 was determined using the Cancer Genome Atlas (TCGA), GTEx, Ualcan, and the Human Protein Altas databases. The Correlation of STRIP2 and survival was detected by PrognoScan and Kaplan–Meier plotter databases. Besides, the correlation between STRIP2 expression and tumor immune infiltration as well as immune checkpoints were analyzed by the ssGSEA method. The biological function of STRIP2 and its co-expression genes was determined by gene ontology (GO) and Genes and Genomes (KEGG), respectively. Finally, the expression level and biological function of STRIP2 in LUAD were determined by qPCR, CCK8, transwell, and wound healing assays.ResultsThis manuscript revealed a significantly increased expression of mRNA and protein of STRIP2 in lung adenocarcinoma compared with the adjacent normal tissues. GEO and Kaplan–Meier plotter databases showed higher STRIP2 expression levels were correlated with poor prognosis survival of LUAD. Moreover, Cox regression analysis suggested that a higher STRIP2 level served as an independent risk factor in predicting deteriorative overall survival (OS) for LUAD patients. SsGSEA results showed STRIP2 expression level was positively correlated with infiltrating levels of Th2 cells in LUAD. Lastly, GO analysis indicated the biological processes were enriched in nuclear division and positive regulation of the cell cycle. KEGG signaling pathway analysis showed STRIP2 was correlated with the MAPK signaling pathway and the TNF signaling pathway. The GSEA database showed that STRIP2 was positively associated with the epithelial–mesenchymal transition, cell cycle, and TNF signaling pathway. The QRT-PCR assay showed that STRIP2 was upregulated in LUAD cell lines. Cell proliferation and migration were inhibited in LUAD by knockdown of STRIP2. Moreover, we confirmed that the TMPO-AS1/let-7c-5p/STRIP2 network regulates STRIP2 overexpression in LUAD and is associated with poor prognosis.ConclusionOur findings indicated that STRIP2 acted as a crucial oncogene in LUAD and was correlated with unfavorable survival and tumor infiltration inflation.

Clinical and radiological predictors of organ preservation in patients with rectal cancer treated with total neoadjuvant therapy.

3619 Background: Baseline rectal MRI is routinely used for tumor staging, selecting the initial treatment and prognostication of patients with rectal adenocarcinoma. However, associations of baseline clinical and MRI variables with organ preservation (OP) in a prospective randomized trial have not been reported. Methods: Patients with MRI staged clinical stage II or III rectal adenocarcinoma treated in a prospective phase II clinical trial were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX) and recommended total mesorectal excision (TME) or watch-and-wait (WW) based on clinical response. The primary outcome was OP, defined as the time from randomization to the clinical decision of TME or last follow-up, whichever occurred first. Clinical variables included: age, sex, race, tumor grade, radiation dose and treatment arm. Radiological variables (evaluated by baseline MRI prior to randomization) included: distance from the anal verge, tumor length, clinical T stage, clinical N stage, relationship to the mesorectal fascia, presence of extramural vascular invasion (EMVI) and mucinous radiographic findings (&gt;50%). Associations of OP with clinical and radiological variables were assessed utilizing the Cox regression model in univariate and multivariate settings. The final multivariate model was chosen using backward selection. Results were analyzed by intention to treat. Results: Case report forms (CRFs) from baseline MRI were available for 289 of 324 randomized patients (89%). Patients with CRFs differed from those without CRFs in race, distance of the tumor from the anal verge and clinical T stage. Median follow-up was 3.4 years. A total of 156 of 324 patients were recommended TME during the study period. The 3-year OP rate was 47%. Independent predictors of OP in the multivariate analysis can be seen in the table. Conclusions: Although the patients included in this analysis may not be fully representative of the entire cohort, our data shows that several radiological variables associated with unfavorable tumor biology – tumor involvement of the mesorectal fascia, presence of EMVI and involved mesorectal nodes – were negatively associated with organ preservation. This information will be useful in selecting rectal cancer patients for WW and should be used for patient stratification in future clinical trials. Clinical trial information: NCT02008656. [Table: see text]

Clinical audit of breast cancer patients under 40 years of age: A single institution experience.

e12533 Background: Age is an important risk factor for breast cancer (BC). The younger age (&lt; 40 years) is associated with unfavorable tumor biology. This is a retrospective analysis of young breast patients treated from 2012-2020 at a comprehensive cancer centre. Methods: Data regarding demography, clinical presentation, histopathological features, molecular profiling, treatment details, and outcomes were retrieved from medical records. All time-to event outcomes were analyzed using Kaplan-Meir method. Results: A total of 134 patients (&lt; 40 years) with BC were included. Median age of the study cohort was 37 years (range: 22-40 years) with a female predominance (98.5%). Most of the patients presented with locally advanced BC (51%) followed by early BC (43%) and metastatic BC (6%). The mean tumor size and positivity lymph nodes of our non-metastatic patients were 3.86±1.90 cm and 3.3±3.98, respectively. The molecular classification revealed most of the patients were of Basal-like BC (TNBC, 40%) followed by Luminal A (33%), Luminal B (14%) and Her-2 (13%), respectively. Germline BRCA testing was positive in 22% patients (10/45). At a median follow-up of 51 months, 3 and 5-year Kaplan-Meier estimates of overall survival were 67.2% and 44.7%, respectively. Conclusions: Breast cancer is a heterogeneous disease with varied survival depending on multiple factors. Early diagnosis and timely appropriate management, as per clinical and molecular profile provides acceptable outcome.

The Effect of Tumor Characteristics and Location on the Extent of Lymph Node Metastases of Head and Neck Cutaneous Squamous Cell Carcinoma.

BackgroundThe extent of a neck dissection for patients with metastasis of cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is still subject to debate and clear guidelines are lacking. Tumor characteristics like size, differentiation and tumor location are known risk factors for lymph node metastasis (LNM). There is some evidence that, depending on tumor location, LNM follows a specific pattern. This study aims to identify which tumor characteristics can predict the pattern and extent of LNM.MethodIn this cohort study 80 patients were included, who underwent a primary neck dissection for LNM of HNcSCC between 2003 and 2018 at the University Medical Center Groningen, the Netherlands. Retrospective data was collected for primary tumor characteristics and LNM and included surgical and follow-up data. Influence of tumor characteristics on the extent of LNM was analyzed using non-parametric tests. Logistic regression analysis were used to identify a metastasis pattern based on the primary tumor location.ResultsOnly primary tumor location was associated with the pattern of LNM. HNcSCC of the ear metastasized to level II (OR = 2.6) and the parotid gland (OR = 3.6). Cutaneous lip carcinoma metastasized to ipsilateral and contralateral level I (OR = 5.3). Posterior scalp tumors showed a metastasis pattern to level II (OR = 5.6); level III (OR = 11.2), level IV (OR = 4.7) and the parotid gland (OR = 10.8). Ear canal tumors showed a low risk of LNM for all levels. The extent of LNM was not related to age or any tumor characteristics i.e. tumor diameter, infiltration depth, differentiation grade, perineural growth and vascular invasion.ConclusionPrimary tumor location determines the LNM pattern. Whereas known unfavorable tumor characteristics did not relate to the extent of LNM. Location guided limited neck dissection combined with parotidectomy will treat most patients adequately.

Abstract No. 262 Recurrence of breast cancer post-cryoablation in candidates previously excluded from clinical trials

Prior breast cryoablation studies have shown promising results for cryoablation for selected low-risk early-stage breast cancer, but many non-surgical candidates are excluded from these clinical trials due to unfavorable patient and tumor characteristics. This study aims to assess ipsilateral breast tumor recurrence (IBTR) after ultrasound (US)-guided percutaneous cryoablation in these suboptimal cryoablation candidates.

Limited impact of COVID-19-related diagnostic delay on cutaneous melanoma and squamous cell carcinoma tumour characteristics: a nationwide pathology registry analysis.

BackgroundThe COVID‐19 pandemic reduced the number of skin cancer diagnoses, potentially causing a progression to unfavourable tumour stages.ObjectivesTo identify the impact of delayed diagnostics on primary invasive melanoma and cutaneous squamous cell carcinoma (cSCC) by comparing tumour (pT) stage, Breslow thickness and invasion depth from before to after the first and second lockdown periods.MethodsIn this population‐based cohort study, histopathology reports registered between 1 January 2018 and 22 July 2021 were obtained from the nationwide histopathology registry in the Netherlands. The Breslow thickness of melanomas, invasion depth of cSCCs, and pT stage for both tumour types were compared across five time periods: (i) pre‐COVID, (ii) first lockdown, (iii) between first and second lockdowns, (iv) second lockdown and (v) after second lockdown. Breslow thickness was compared using an independent t‐test. pT‐stage groups were compared using a χ2‐test. Outcomes were corrected for multiple testing using the false discovery rate.ResultsIn total, 20 434 primary invasive melanomas and 68 832 cSCCs were included in this study. The mean primary melanoma Breslow thickness of the prepandemic era (period i) and the following time periods (ii–v) showed no significant difference. A small shift was found towards unfavourable pT stages during the first lockdown compared with the pre‐COVID period: pT1 52·3% vs. 58·6%, pT2 18·9% vs. 17·8%, pT3 13·2% vs. 11·0%, pT4 9·1% vs. 7·3% (P = 0·001). No relevant changes were seen in subsequent periods. No significant change in pT stage distribution was observed between the pre‐COVID (i) and COVID‐affected periods (ii–v) for cSCCs.ConclusionsTo date, the diagnostic delay caused by COVID‐19 has not resulted in relatively more unfavourable primary tumour characteristics of melanoma or cSCC. Follow‐up studies in the coming years are needed to identify a potential impact on staging distribution and survival in the long term.

Risk Factors for Xerostomia Following Radiotherapy of Head-and-Neck Cancers.

Many head-and-neck cancer patients receive radiotherapy, which may be associated with significant toxicities. Xerostomia is considered one of the most debilitating late adverse events. This study was performed to identify risk factors for xerostomia. Several characteristics were investigated for associations with late xerostomia in 159 patients irradiated for head-and-neck cancer including age, sex, tumor site and size, underlying pathology, histologic grading, upfront resection, systemic treatment, and type and dose of radiotherapy. Ninety (57%) and 35 (22%) patients experienced grade ≥2 and ≥3 xerostomia, respectively. Grade ≥2 xerostomia was significantly associated with tumor site (nasopharynx/oropharynx/oral cavity/floor of mouth, p=0.049). Grade ≥3 xerostomia was significantly associated with age ≥61 years (p=0.035); trends were found for tumor site (p=0.088), bilateral nodal involvement (p=0.093), definitive treatment (p=0.082), and systemic treatment (p=0.055). Risk factors for xerostomia following radiotherapy of head-and-neck cancers were identified including older age, unfavorable tumor site, bilateral involvement of lymph nodes, definitive treatment, and addition of systemic therapies. For patients with risk factors, sparing of the salivary glands is particularly important.

COMMD2 Upregulation Mediated by an ncRNA Axis Correlates With an Unfavorable Prognosis and Tumor Immune Infiltration in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) seriously endangers the health and quality of life of individuals worldwide. Increasing evidence has underscored that the copper metabolism MURR1 domain (COMMD) family plays important roles in tumorigenesis. However, the specific role, biological function, mechanism and prognostic value of COMMD2 and its correlation with immune cell infiltration in LIHC remain unknown. In this study, we first determined the expression and prognostic potential of COMMD2 in human tumors using The Cancer Genome Atlas (TCGA) data and identified COMMD2 as a potential oncogene in LIHC. High COMMD2 expression was associated with pathological tumor stage and metastasis. Subsequently, noncoding RNAs (ncRNAs) upregulating COMMD2 expression were identified by performing expression, correlation, and survival analyses in combination. The CRNDE/LINC00511/SNHG17/HCG18-miR-29c-3p axis was identified as the most likely ncRNA-associated pathway upstream of COMMD2 in LIHC. Next, the expression profiles of COMMD2 and ncRNAs were validated in LIHC tissues and adjacent normal tissues. Furthermore, COMMD2 was significantly positively correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint molecule expression. Importantly, COMMD2 potentially influenced prognosis by regulating immune cell infiltration in LIHC. Finally, COMMD2 was knocked down in LIHC cell lines using siRNAs for functional assays in vitro, resulting in suppressed cell proliferation and migration. In summary, our findings showed that the ncRNA-mediated upregulation of COMMD2 was associated with an unfavorable prognosis correlated with immune cell infiltration in LIHC.

Nanodrug simultaneously regulates stromal extracellular matrix and glucose metabolism for effective immunotherapy against orthotopic pancreatic cancer

The extremely dense stromal extracellular matrix (ECM) and low glucose level affect the infiltration and effector functions of antitumor immune cells, respectively, which remain two concurrent main hurdles for achieving effective immunotherapy in pancreatic tumor. It has been found that the C-X-C motif chemokine ligand 1 (CXCL1) gene negatively regulates the stromal ECM formation, while the glucose transporter 1 (GLUT1) gene mediates aberrant glucose metabolism to restrict the glucose supply to antitumor immune cells. Here, in order to restore the anti-tumor immunity for effective immunotherapy against the pancreatic tumor, a pH-sensitive and mesothelin-targeting nanodrug incorporating CXCL1 siRNA and PI3K signaling inhibitor wortmannin (WT) was prepared. Owing to its unique structural design, the nanodrug showed advantages to accumulate in and penetrate the orthotopic pancreatic tumor. Consequently, silencing the CXCL1 gene inhibited the stromal ECM formation to promote tumor infiltration of antitumor immune cells, and suppressing GLUT1 through PI3K inhibition blocked the glycolysis of cancer cells and tumor-associated macrophages (TAMs) to increase the intratumor glucose level for sustained effector functions of antitumor immune cells. In murine orthotopic pancreatic tumor model, this multifunctional nanodrug mediated strong synergistic effect of CXCL1 siRNA and WT to remodel the unfavorable tumor immunosuppressive microenvironment (TME), which dramatically boosted the therapeutic efficacy of immune checkpoint blockade in this highly malignant and immunologically “cold” tumor.

Association of pSTAT3, pSyk with c-Myc, p53, BCL2 proteins expression and survival of patients with diffuse large B-cell lymphoma

Background . Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin’s lymphomas. The effectiveness of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) therapy was observed in about 60 % of patients, in 20–30 % of cases DLBCL is characterized by a refractory course. Standard clinical prognostic criteria do not accurately determine the prognosis of the disease. In this regard, the problem of developing additional predictors of DLBCL course remains relevant today and is directly related to the molecular pathogenesis of the disease. The objective : to determine the relationship of pSTAT3, pSyk with c-Myc, p53, BCL2 oncoproteins expression and survival of DLBCL patients. Materials and methods . Biopsy specimens of lymph nodes and other organs and tissues obtained from 100 patients with newly diagnosed DLBCL were used for the study. All patients received standard first-line immunochemotherapy according to the R-CHOP regimen. Determination of the relative amount of tumor cells expressing pSTAT3, pSyk was carried out using immunohistochemical and morphometric methods. The threshold value of proteins expression was calculated using the ROC analysis: for pSTAT3 it was 68 % of positive tumor cells, for pSyk – 28 %. The relationship of pSTAT3, pSyk with c-Myc, p53, BCL2 expression was determined using the Pearson χ2 test. Overall (OS) and progression-free (PFS) survival were calculated using the Kaplan–Meier method (log-rank test). Results . The suprathreshold pSTAT3 expression was found to be associated with a high content of c-Myc and p53 transcription factors in tumor cells (p = 0.015 and p = 0.010, respectively). In the group of patients with isolated overexpression of pSTAT3, the 5-year OS and PFS were lower, and the risk of death and disease progression was almost 1.5 times higher than in patients with low protein expression (p = 0.015 and p = 0.011, respectively). When studying the co-expression of pSTAT3 and pSyk, the lowest OS and PFS were recorded in the subjects with a simultaneous high expression of these proteins. With this combination of markers, the probability of an adverse event in patients when calculating OS increased by 2.9 times (p = 0.003; hazard ratio 2.9; 95 % confidence interval 1.43–5.85), and when analyzing PFS – by 2.3 times (p = 0.021; hazard ratio 2.3; 95 % confidence interval 1.14–4.87) compared with other variants of their simultaneous expression. Conclusion . Overexpression of pSTAT3 is associated with unfavorable biological tumor characteristics and poor patient survival. The combined suprathreshold expression of the pSTAT3 and pSyk proteins is associated with lower OS and PFS values compared to their isolated expression.